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INFLUENCE OF GENETIC ADMIXTURE ON POLYMORPHISMS OF ALCOHOL-METABOLIZING ENZYMES: ANALYSES OF MUTATIONS ON THE CYP2E1, ADH2, ADH3 AND ALDH2 GENES IN A MEXICAN–AMERICAN POPULATION LIVING IN THE LOS ANGELES AREA

Tamiko Konishi, James Lafayette Smith, Keh-Ming Lin, Yu-Jui Yvonne Wan
DOI: http://dx.doi.org/10.1093/alcalc/agg021 93-94 First published online: 1 January 2003

In pre-Columbian times, the population of Mexico was totally indigenous or Amerindian. When Columbus arrived in the New World, and Cortez marched from Vera Cruz into the Valley of Mexico, a whole new element of genes was introduced into the existing populations. They were a diverse set of genes reflecting Europe and Africa. Today, Mexican– Americans are estimated to be derived from Native Americans by 31%, Spanish by 61%, and African by 8% (Hanis et al., 1991).

Alcohol dehydrogenase 2 (ADH2), alcohol dehydrogenase 3 (ADH3), aldehyde dehydrogenase 2 (ALDH2) and cytochrome P450 2E1 (CYP2E1) are the main alcohol-metabolizing enzymes. These enzyme-encoded genes are polymorphic at several loci and therefore affect enzyme activities. The frequency of gene polymorphisms varies among different ethnic groups. For example, the ALDH2*2 allele, which is responsible for flushing and aversive reactions upon ethanol consumption, is very common in Asians (23–36%) and South American Indians (41–43%) (Goedde et al., 1984; Shen et al., 1997). The frequencies of the ADH2*2 and ADH3*1 alleles, which have been considered to be protective alleles against excessive drinking, are also significantly higher in Asians (70 and 95%, respectively) than Caucasians (4 and 56%, respectively) (Shen et al., 1997). In addition, the CYP2E1 RsaI c2 allele, which is believed to be associated with increased enzyme activity, is also more common in Asians (17–28%) than in African–Americans and Caucasians (<5%) (Stephens et al., 1994). Despite the higher prevalence of heavy drinking and alcohol-related problems among Mexican–American than other ethnic groups in the USA (Caetano, 1983), few alcohol pharmacogenetic studies in this population have been performed. We therefore examined the genotype of these alcohol-metabolizing enzyme genes in this major minority population residing in Southern California, to determine if Mexican–Americans carry any of those protective alleles against alcohol drinking.

Blood samples were obtained from 251 healthy individuals. They included 105 men (mean age ± SD: 32.15 ± 9.17 years) and 146 women (31.90 ± 9.03 years) who had been recruited for previous studies (Wan et al., 1998; Mendoza et al., 2001). All individuals had homogeneous Mexican backgrounds and were defined as having at least three of the four biological parents of the same ethnicity. Genomic DNA was extracted and used for analysing the genetic polymorphisms of ADH2, ADH3, ALDH2 and CYP2E1 by the polymerase-chain reaction followed by restriction enzyme digestion. The distribution and the frequencies of these alleles in this population show a unique ethnic specificity. Mexican–Americans have very low frequencies of the protective ADH2*2 (5%) and ALDH2*2 (0.6%) alleles (Table 1), which are similar to that of Africans and Caucasians. The frequency of the ADH3*1 allele, another protective allele, is also lower in Mexican– Americans (66%) than in Asians (95%). The frequencies for the RsaI (c2), DraI (C) and TaqI (A1) of the CYP2E1 gene are 14.3, 16.9 and 18.7%, respectively, which are in between the frequencies of Caucasians/African–Americans (1–8%) and Asians (17–28%) (Table 1). The CYP2E1 RsaI c2 allele frequency is similar between Mexican–Americans and Nicaraguans (Martinez et al., 1998). These data, which contain the largest sample size and a complete allele profile, not only confirm our previous findings (Wan et al., 1998), but also suggest that, without the restraining effects of ADH2*2, ADH3*1 and ALDH2*2, Mexican–Americans may be able to consume large quantities of ethanol. In addition, the presence of the CYP2E1 c2 allele may enhance alcohol metabolism. Moreover, the CYP2E1 genotyping results reflect the fact that Mexican–Americans came from a mixture of two or more population groups that have very different allele frequencies and this genetic mixture might give rise to large interethnic differences at a functional level.

View this table:
Table 1.

The allele frequencies of CYP2E1 RsaI c2, DraI C, and TaqI A1, ADH2*2, ADH3*1 and ALDH2*2 in different ethnic groups

Ethnic groupCYP2E1RsaI c2(%)CYP2E1DraI C (%)CYP2E1TaqI (%)ADH2*2 (%)ADH3*1 (%)ALDH2*2 (%)
a Stephens et al.(1994); b Goedde et al.(1992); c Shen et al.(1997); d Wong et al.(2000); e Borras et al.(2000); f Goedde et al.(1986); g Goedde et al.(1984); h Wall et al.(1997); i Lisker-Yourkowitzky et al.(1995); j Martinez et al.(1998).
Africans 1a 8aA1 0b 0b
Asians17–28a24a68–71c92–95c23–36c
Caucasians 3d10d14d 4e56e 0b,f
South American Indians41–43g
North American Indians 0h56h 2–5f
Mexican Indians or Mexicans 3i 0–4f,i
Mexican–Americans in Los Angeles (current study)141719 566 0.6
Nicaraguan17j

Acknowledgments

The work was supported by grants from NIAAA RO1 AA12081 and RO1 AA12081-02S1.

Footnotes

  • * Author to whom correspondence should be addressed at: Department of Pathology, Harbor-UCLA Medical Center, 1000 West Carson Street, Torrance, CA 90509, USA.

REFERENCES